In rhesus macaques, a SIV/HIV-1 chimeric virus (SHIV) containing the env gene from HIV-1 89.6 is capable of initiating a systemic infection following mucosal or systemic inoculation. Previous Infection with SHIV89.6 protects 60% of rhesus monkeys from uncontrolled replication of SIVmac239 after intravaginal inoculation. Understanding the nature and anatomic location of the adaptive immune that confers protection to SHIV "immunized" monkeys would be significant contribution to AIDS vaccine development. In project by Miller we will define the SIV-specific T cell and B cell responses in the blood, genital secretions, cervicovaginal and lymphoid tissues of SHIV-immunized animals before and after SIVmac239 challenge; define the effect of Depo-Provera treatment 4 weeks prior to SIV challenge on SIV-specific T cell and B cell responses in the blood, genital secretions, cervicovaginal and lymphoid tissues of SHIV-immunized animals before and after SIVmac239 challenge; define the effect of T cell and B cell depletion just prior to SIVmac239 challenge on live-attenuated vaccine efficacy and SIV-specific T cell and B cell responses in the blood and genital secretions just before and after SIV challenge, define the effect of T cell costimulatory blockade (CTLA4-lg/anti-CD40) at the time of SIVmac239 challenge on live-attenuated vaccine efficacy and SIV-specific T cell and B cell responses in the blood and genital secretions just before and after SIV challenge, Finally we will define the effect of anti-inflammatory therapy with anti-IL1-beta (Kineret(R)) and anti-TNF alpha (Humira(R)) just prior to SIVmac239 challenge on live-attenuated vaccine efficacy and SIV-specific T cell and B cell responses in the blood and genital secretions. These studies should provide considerable insight into the role of adaptive antiviral immunity in live-attenuated lentiviral vaccine mediated protection.